APC and Retinoic Acid Biosynthesis in Cancer and Development

One type of inherited colon cancer predisposition, familial adenomatous polyposis (FAP), results from mutations in a single gene known as adenomatous polyposis coli (APC). Recent studies from the our laboratory indicate that APC may promote colonocyte differentiation by stimulating the production of retinoic acid. Retinoic acid is a lipid mediator with important roles in controlling cell patterning, fate and differentiation. Central to the ability of a cell to respond to retinoic acid is the requirement of first converting dietary retinol (vitamin A) into retinoic acid, a process that occurs via two enzymatic steps. The first step of this process converts retinol into retinal and is mediated by alcohol dehydrogenases (ADH) and short chain dehydrogenases (SDR). The second step involves conversion of retinal into retinoic acid via aldehyde dehydrogenases (ALDH). Given the required conversion of vitamin A, retinoic acid production is limited to cells harboring the necessary biosynthetic enzymes. We demonstrated that while colon adenomas and carcinomas have elevated ?-catenin target genes, they also showed a deficiency of retinoic acid biosynthetic enzymes. In establishing a link between APC and control of retinoic acid biosynthesis, introduction of APC into an APC-mutant colon carcinoma cell line increased retinoic acid biosynthesis in parallel with the transcriptional induction of retinol dehydrogenase L (RDHL) .